Prefrontal cortex (PFC) is a brain region critically involved in the control of high-level "executive" processes including information storage, complex reasoning, novelty seeking and emotional control. Functions of PFC neurons are strongly influenced by dopaminergic inputs. Aberrant dopaminergic actions have been implicated in PFC abnormalities associated with mental disorders such as schizophrenia. Several lines of evidence suggest that the dopamine D4 receptor, which is highly enriched in PFC neurons, plays an important and unique role in regulating PFC functions. However, little is known about the cellular mechanisms and functional consequences of D4 receptor-mediated signaling in PFC circuits. The long-term goal of this project is to understand the physiological functions of D4 receptors in PFC neurons. Particularly, we would like to elucidate how D4 signaling is involved in the regulation of synaptic transmission and plasticity in PFC, which is critical for cognitive and emotional processes. We hypothesize that D4 receptors exert an important impact on PFC functions by regulating the multifunctional Ca2+/calmodulin -dependent protein kinase II (CaMKII) and the downstream NMDA and AMPA type glutamate receptor channels. In agreement with this hypothesis, we have found that D4 receptors exert a dynamic regulation of CaMKII activity and translocation, and modulate NMDA receptor-mediated ionic and synaptic currents in a CaMKII-dependent manner. Moreover, AMPA receptor-mediated transmission and AMPA receptor internalization are also strongly regulated by D4 receptor activation. Combined electrophysiological, pharmacological, biochemical and molecular analyses will be used to extend these studies. This proposal will investigate novel mechanisms for D4 receptors to modulate PFC neuronal activity. Elucidation of these mechanisms would provide a framework for understanding how the dopaminergic and glutamatergic systems may be mechanistically linked. Such knowledge would not only offer important insights into functional roles of D4 receptors in normal PFC network, but also shed light on the development of new pharmacological agents for the treatment of many diseases associated with dopaminergic dysfunction in PFC.